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NADP isocitrate dehydrogenase 1 (isocitrate dehydrogenase [NADP] cytoplasmic, IDH1)

Function: - catalyzes reversable conversion of isocitrate to 2-oxoglutarate isocitrate + NADP+ 2-oxoglutarate + CO2 + NADPH Cofactor: binds 1 Mg+2 or Mn+2 per subunit Structure: - homodimer - belongs to the isocitrate & isopropylmalate dehydrogenases family Compartment: cytoplasm, peroxisome Pathology: - IDH1 gene mutation - IDH1 R132H mutation, with codeletion of 1p & 19q seen in a case of recurrent oligodendroglioma [3] - IDH1-mutation in acute myeloid leukemia (AML) [4] - addition of IDH1 inhibitor ivosidenib (Tibsovo) to azacitidine increases survival 3-fold [4] Pharmacology: - ivosidenib inhibits mutant IDH1 in relapsed or refractory acute myeloid leukemia (AML) with IDH1 gene mutation - vorasidenib (Servier) inhibits mutant IDH1 investigational treatment of gliomas with IDH1 gene mutation

General

metalloprotein NADP isocitrate dehydrogenase

Properties

SIZE: entity length = 414 aa MW = 47 kD COMPARTMENT: peroxisome cytoplasm MOTIF: cofactor-binding site [75-77] COFACTOR-BOUND: NADP MOTIF: binding site SITE: 77-77 FOR-BINDING-OF: Substrate cofactor-binding site [82-82] COFACTOR-BOUND: NADP Substrate binding {94-100} binding site SITE: 109-109 FOR-BINDING-OF: Substrate binding site SITE: 132-132 FOR-BINDING-OF: Substrate tyrosine residue {139} lysine residue {212} manganese [Mn]-binding site SITE: 252-252 cofactor-binding site [260-260] COFACTOR-BOUND: NADP manganese [Mn]-binding site SITE: 275-275 cofactor-binding site [310-315] COFACTOR-BOUND: NADP cofactor-binding site [328-328] COFACTOR-BOUND: NADP

Database Correlations

OMIM 147700 UniProt O75874 Pfam PF00180 KEGG correlations ENZYME 1.1.1.42

References

  1. UniProt :accession O75874
  2. Wikipedia, isocitrate dehydrogenase entry http://en.wikipedia.org/wiki/isocitrate_dehydrogenase
  3. Chi AS, Cahill DP, Larvie M, Louis DN Case 38-2016 - A 52-Year-Old Woman with Recurrent Oligodendroglioma. N Engl J Med 2016; 375:2381-2389. December 15, 2016 PMID: 27974037 http://www.nejm.org/doi/full/10.1056/NEJMcpc1610101
  4. Ingram I Upfront IDH1 Inhibitor Triples Survival in Older AML. Median OS for ivosidenib-azacitidine reached 2 years in patients ineligible for intensive therapy. MedPage Today December 11, 2021 https://www.medpagetoday.com/meetingcoverage/ashhematology/96149